[go: up one dir, main page]

US2595334A - Benzothiazolesulfonamides and method of preparing the same - Google Patents

Benzothiazolesulfonamides and method of preparing the same Download PDF

Info

Publication number
US2595334A
US2595334A US154884A US15488450A US2595334A US 2595334 A US2595334 A US 2595334A US 154884 A US154884 A US 154884A US 15488450 A US15488450 A US 15488450A US 2595334 A US2595334 A US 2595334A
Authority
US
United States
Prior art keywords
water
preparing
filtered
compounds
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US154884A
Inventor
James W Clapp
Jr Richard O Roblin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Holdings LLC
Original Assignee
American Cyanamid Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to US154884A priority Critical patent/US2595334A/en
Application granted granted Critical
Publication of US2595334A publication Critical patent/US2595334A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62Benzothiazoles
    • C07D277/68Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70Sulfur atoms
    • C07D277/76Sulfur atoms attached to a second hetero atom
    • C07D277/80Sulfur atoms attached to a second hetero atom to a nitrogen atom

Definitions

  • This invention relates to substituted benzothiazolesulfonamides and to methods of preparin'g's'aid compounds.
  • the compounds of the present invention are, in general, white crystalline solids, soluble inmost organic solvents and having definite melting points.
  • the compounds are prepared by dissolving a mercapto-benzothiazole in an aqueous acid solution and passing in chlorine gas to produce the corresponding sulfonyl chloride. This product is then treated with an excess of ammonia in the excess salt and water. These agents, for the most administered in adequate doses.
  • R and R are hydrogen, alkyl or heterocyclic radicals.
  • the benzene portion of the benzothiazole nucleus may also have present sub- ,requires a large excess of chlorine.
  • the reaction time is not particularly critical but chlorine should. be added at such a rate that the temperature does not rise excessively and until an excess is present in the reaction mixture.
  • the temperature duringjthe chlorination is preferably maintained within the range of -l0 C. to 25 C. However, during the reaction of the sulfonyl chloride with ammonia or an amine, the
  • temperature may be increased to about C., de-
  • the compounds of the present invention are active against certain micro-organisms and are also highly efiective as inhibitors of carbonic anhydrase and for this reason, may be effective in the relief of edema associated with. congestive heart failure or in other conditions where inhibition of carbonic anhydrase is useful.
  • EXAMPLE 1 V 2benzothiazolesulfonamide parts of Z-mercaptobenzothiazole (powdered) are suspended in a mixture of 550 parts of glacial acetic acid and 1100 parts of water. This mixture is stirred rapidly in a cooling bath while chlorine is introduced in multiple fine "streams at a rapid rate for about three hours. The temperature of the mixture is heldbelow 8-,C. to minimize decomposition. The-chlorine treatment isfcontinued until a test of the suspended solid shows it to be mostly soluble in ethylene chloride; this The crude product is unstable at ordinary temperatures, but
  • the filtrate is neutralized with acid; the product slowly crystallizes. It is filtered. and again extracted with dilute alkali and filtered. Acidification of the filtrate again gives slow crystallization.
  • the product is filtered, dried, and recrystallized from ethylene chlorigle three times. The pure compound is a while crystalline solid, melting point 148-153 C. (not sharp), with charring and bubbling. As thus produced it is a hemihydrate.
  • R is a lower alkyl radical
  • R and R are members of the group consisting of hydrogen, lower alkyl and 2-thiazolyl radicals which comprises reacting a mercaptobenzothiazole with chlorine in the presence of an aqueous acid solution and subsequently with a member of the group consisting of ammonia, a lower alkyl amine and Z-aminothiazole.
  • a method of preparing Z-benzothiazolesulfon-di-n-butylamide which comprises dissolving 2-mercaptobenzothiazole in aqueous acetic acid solution, passing chlorine into said solution, mixing the resulting product with di-n-butylamine and recovering the said product therefrom.
  • a method of preparing N-(Z-thiazolyD- benzothiazole v2 sulfonamide which comprises dissolving Z-mercaptobenzothiazole in aqueous acid solution, passing chlorine into said solution,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Description

Patented May 6, 1952 BEN ZOTHIAZOLESULFONAMIDES AND METHOD OF PREPARING THE SAME James W. Clapp, Darien, and Richard 0. Roblin, Jr., Riverside, Conn., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application April 8, 1950,
Serial No. 154,884
This invention relates to substituted benzothiazolesulfonamides and to methods of preparin'g's'aid compounds.
It is generally recognized that numerous functions and actions of the human body are largely controlled by a wide variety of enzymes. One of these numerous enzymes is called carbonic anhydrase because it is involved in the metabolism of carbon dioxide. This enzyme has other functions too, since it can catalyze the conversion of carbon dioxide to carbonic acid. The excretion of acid by the kidneys is thought to be due to this function of carbonic anhydrase.
The excretion of acid by the kidneys is one method by which the body normally conserves salt. The maintenance of a constant ratio of salt to water in the body is of utmost importance for general health. In some cases, however,-excess salt and water accumulate in the tissues causing a condition which is called edema. It is frequently encountered in association withfcon gestiveheart failure. The excess salt and water cause an uncomfortable swelling of the tissues and place an added strain on the heart. To combat this condition so-called diuretic agents are sometimes used to promote the excretion of the 12 Claims. (Cl. 260306.6)
2 stituents such as halogen, alkyl, alkoxy, hydroxyl and the like.
The compounds of the present invention are, in general, white crystalline solids, soluble inmost organic solvents and having definite melting points.
The compounds are prepared by dissolving a mercapto-benzothiazole in an aqueous acid solution and passing in chlorine gas to produce the corresponding sulfonyl chloride. This product is then treated with an excess of ammonia in the excess salt and water. These agents, for the most administered in adequate doses.
We have now found that substituted benzo- 'thiazolesulfonamides show much greater activity than sulfanilamide in inhibiting carbonic anhydrase. These compounds are new and may be illustrated by the following general formula:
'/CS 02N\ N in which R and R are hydrogen, alkyl or heterocyclic radicals. The benzene portion of the benzothiazole nucleus may also have present sub- ,requires a large excess of chlorine.
form of liquid ammonia or ammonium hydroxide to produce the unsubstituted sulfonamides and with an alkylamine or a heterocyclic amine to produce compounds substituted on the. sulfonamide group. 7 j
The reaction time is not particularly critical but chlorine should. be added at such a rate that the temperature does not rise excessively and until an excess is present in the reaction mixture. The temperature duringjthe chlorination is preferably maintained within the range of -l0 C. to 25 C. However, during the reaction of the sulfonyl chloride with ammonia or an amine, the
= temperature may be increased to about C., de-
pending upon the volatility of the particular amine. Obviously the reaction should be carried out at a temperature below the boiling pointof the amine. Q 4
The compounds of the present invention are active against certain micro-organisms and are also highly efiective as inhibitors of carbonic anhydrase and for this reason, may be effective in the relief of edema associated with. congestive heart failure or in other conditions where inhibition of carbonic anhydrase is useful.
The following examples illustrate the preparation of representative benzothiazolesulfonamides from the corresponding mercaptobenzothiazole. All parts are by weight unless otherwise indicated.
EXAMPLE 1 V 2benzothiazolesulfonamide parts of Z-mercaptobenzothiazole (powdered) are suspended in a mixture of 550 parts of glacial acetic acid and 1100 parts of water. This mixture is stirred rapidly in a cooling bath while chlorine is introduced in multiple fine "streams at a rapid rate for about three hours. The temperature of the mixture is heldbelow 8-,C. to minimize decomposition. The-chlorine treatment isfcontinued until a test of the suspended solid shows it to be mostly soluble in ethylene chloride; this The crude product is unstable at ordinary temperatures, but
is more stable after purification. The crude 2- benzothiazolesulfonyl chloride is then filtered and washed thoroughly with ice-cold water. It can be recrystallized from a large volume of ether or petroleum ether and when pure it forms white crystals, melting point 108-110 C.
30 parts of damp 2-benzothiazolesulfonyl chloride is added to 60 parts of concentrated ammonium hydroxide (d=0.90) with good stirring. The temperature of the mixture is not critical up to at least 40 C. The mixture is stirred for one to two hours, then filtered. The filtrate is treated with activated charcoal, then refiltered, and the product precipitated by neutralization, filtered, washed with water and dried. It is purified by recrystallization from ethylene chloride or from a large volume of water or by repeated solution in dilute alkali and reprecipitation with acid. Impurities are removed from solution with activated charcoal. The pure product is a white crystalline solid, melting point 1'77.5 0., with bubbling. The yield based on 2-mercaptobenzothiazo1e was about 36%.
The yields are improved somewhat by the use of excess anhydrous liquid ammonia for reaction with the sulfonyl chloride. The excess ammonia is then allowed to evaporate and the crude sulfonamide is purified as indicated above. Yields up to 58% (crude) are obtained by this method.
EXAMPLE 2 2-benzothiazolesulfon-n-propylamide Six parts of purified Z-benzothiazolesulfonyl chloride are added gradually to 50 parts of dry n-propylamine, with stirring and chilling. The mixture is stirred for an additional period and the excess amine then evaporated. The residue is triturated with water to produce crystallization. The solid is filtered and washed with water, then redissolved in an excess of dilute sodium hydroxide. The solution is treated with activated charcoal, filtered, and neutralized with acid. The precipitate is filtered, washed with water, and dried, then recrystallized from a large volume of carbon tetrachloride. Yield, 96% of theoretical. The pure product is a white, crystalline solid, melting point 101-101.5 C. It is soluble in ethyl acetate, ethylene chloride, benzene, hot carbon tetrachloride and hot hexane.
EXAMPLE 3 2wbenzothiaeolesulfiovi-di-n-butyiamicie EXAMPLE 4 N-(2 thiazolyZ) benzothiazole- Z-sulfonamide 7.4parts of purified Z-benzothiazole sulfonyl chloride are added gradually to a mixture of 20 parts of 2-aminothiazole and 50 parts of dry pryidine with stirring and chilling. Solution is soon complete. Stirring is continued for about hour without chilling, and the mixture allowed to stand for two days. Water is added, precipitating a gum. The mixture is acidified, and the gum then washed well with water. It is then extracted with dilute alkali, and filtered. The filtrate is neutralized with acid; the product slowly crystallizes. It is filtered. and again extracted with dilute alkali and filtered. Acidification of the filtrate again gives slow crystallization. The product is filtered, dried, and recrystallized from ethylene chlorigle three times. The pure compound is a while crystalline solid, melting point 148-153 C. (not sharp), with charring and bubbling. As thus produced it is a hemihydrate.
We claim:
1. Compounds of the group consisting of those having the general formula:
in which R and R. are members of the group consisting of hydrogen, lower alkyl and Z-thiazolyl radicals.
2. Compounds of the group consisting of those having the general formula:
s p o-s omen in which R is a lower alkyl radical.
3. 2-benzothiazolesulfonamide. 4. 2-benzothiazolesulfon-n-propylamide. 5. Z-benzothiazolesulfon-di-n-butylamide. 6. N- (2-thiazolyl) benzothiazole-2-sulfonamide. 7. A method of preparing compounds having the general formula:
/CSO2N N/ .RI
in which R and R are members of the group consisting of hydrogen, lower alkyl and 2-thiazolyl radicals which comprises reacting a mercaptobenzothiazole with chlorine in the presence of an aqueous acid solution and subsequently with a member of the group consisting of ammonia, a lower alkyl amine and Z-aminothiazole. 8. A method of preparing compounds having the general formula:
mixing the resulting product with N-propylamine and recovering said compound therefrom.
11. A method of preparing Z-benzothiazolesulfon-di-n-butylamide which comprises dissolving 2-mercaptobenzothiazole in aqueous acetic acid solution, passing chlorine into said solution, mixing the resulting product with di-n-butylamine and recovering the said product therefrom.
12. A method of preparing N-(Z-thiazolyD- benzothiazole v2 sulfonamide which comprises dissolving Z-mercaptobenzothiazole in aqueous acid solution, passing chlorine into said solution,
mixing the resulting product with Z-aminothiazole and recovering said product therefrom.
,JAMES W. CLAPP.
RICHARD O. ROBLIN, JR.
REFEREFHJES CITED file of this patent:
Number UNITED STATES PATENTS Name Date Roblin Jan. 9, 1945

Claims (1)

1. COMPOUNDS OF THE GROUP CONSISTING OF THOSE HAVING THE GENERAL FORMULA:
US154884A 1950-04-08 1950-04-08 Benzothiazolesulfonamides and method of preparing the same Expired - Lifetime US2595334A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US154884A US2595334A (en) 1950-04-08 1950-04-08 Benzothiazolesulfonamides and method of preparing the same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US154884A US2595334A (en) 1950-04-08 1950-04-08 Benzothiazolesulfonamides and method of preparing the same

Publications (1)

Publication Number Publication Date
US2595334A true US2595334A (en) 1952-05-06

Family

ID=22553226

Family Applications (1)

Application Number Title Priority Date Filing Date
US154884A Expired - Lifetime US2595334A (en) 1950-04-08 1950-04-08 Benzothiazolesulfonamides and method of preparing the same

Country Status (1)

Country Link
US (1) US2595334A (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2868800A (en) * 1954-10-13 1959-01-13 Upjohn Co 6-ethoxybenzothiazole-2-sulfonamide
US2891960A (en) * 1956-11-03 1959-06-23 Hoechst Ag Benzothiazol-2-sulfonyl-ureas and a process for their manufacture
DE1103341B (en) * 1957-04-04 1961-03-30 Omikron Gagliardi Societa Di F Process for the preparation of heterocyclic sulfohalides
US2980679A (en) * 1957-04-04 1961-04-18 Omikron Gagliardi Societa Di F Process for preparing heterocyclic sulfonamides
US3020287A (en) * 1958-06-05 1962-02-06 Firestone Tire & Rubber Co Nu-(propynyl)-2-(thiazole) sulfenamides
US3139436A (en) * 1958-06-09 1964-06-30 Merck & Co Inc Nu-2-benzothiazolylsulfonylbenzamide
US3147420A (en) * 1958-02-10 1964-09-01 Albert A Mros Electric motor braking control system
US3190942A (en) * 1955-06-17 1965-06-22 Goodyear Tire & Rubber Cyanoalkyl arylenethiazolesulfenamide accelerators
US3216981A (en) * 1956-10-22 1965-11-09 Monsanto Co Cyanoalkylthiazolesulfenamides
EP0070239A1 (en) * 1981-07-13 1983-01-19 Merck & Co. Inc. Benzothiazolesulfonamide derivatives, their preparation and ophthalmic compositions containing said derivatives
EP0079269A1 (en) * 1981-11-03 1983-05-18 Merck & Co. Inc. Hydroxy-substituted-2-benzothiazolesulfonamide for the topical treatment of elevated intraocular pressure
US4416890A (en) * 1981-07-13 1983-11-22 Merck & Co., Inc. Benzothiazolesulfonamide derivatives for the topical treatment of elevated intraocular pressure
US4426388A (en) 1982-04-02 1984-01-17 Merck & Co., Inc. 5-Benzothiazolesulfonamide derivatives for the topical treatment of elevated intraocular pressure

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2367058A (en) * 1942-07-31 1945-01-09 American Cyanamid Co Pyridine-3-sulphonamide derivatives and processes for their production

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2367058A (en) * 1942-07-31 1945-01-09 American Cyanamid Co Pyridine-3-sulphonamide derivatives and processes for their production

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2868800A (en) * 1954-10-13 1959-01-13 Upjohn Co 6-ethoxybenzothiazole-2-sulfonamide
US3190942A (en) * 1955-06-17 1965-06-22 Goodyear Tire & Rubber Cyanoalkyl arylenethiazolesulfenamide accelerators
US3216981A (en) * 1956-10-22 1965-11-09 Monsanto Co Cyanoalkylthiazolesulfenamides
US2891960A (en) * 1956-11-03 1959-06-23 Hoechst Ag Benzothiazol-2-sulfonyl-ureas and a process for their manufacture
DE1103341B (en) * 1957-04-04 1961-03-30 Omikron Gagliardi Societa Di F Process for the preparation of heterocyclic sulfohalides
US2980679A (en) * 1957-04-04 1961-04-18 Omikron Gagliardi Societa Di F Process for preparing heterocyclic sulfonamides
US3147420A (en) * 1958-02-10 1964-09-01 Albert A Mros Electric motor braking control system
US3020287A (en) * 1958-06-05 1962-02-06 Firestone Tire & Rubber Co Nu-(propynyl)-2-(thiazole) sulfenamides
US3139436A (en) * 1958-06-09 1964-06-30 Merck & Co Inc Nu-2-benzothiazolylsulfonylbenzamide
EP0070239A1 (en) * 1981-07-13 1983-01-19 Merck & Co. Inc. Benzothiazolesulfonamide derivatives, their preparation and ophthalmic compositions containing said derivatives
US4416890A (en) * 1981-07-13 1983-11-22 Merck & Co., Inc. Benzothiazolesulfonamide derivatives for the topical treatment of elevated intraocular pressure
EP0079269A1 (en) * 1981-11-03 1983-05-18 Merck & Co. Inc. Hydroxy-substituted-2-benzothiazolesulfonamide for the topical treatment of elevated intraocular pressure
US4426388A (en) 1982-04-02 1984-01-17 Merck & Co., Inc. 5-Benzothiazolesulfonamide derivatives for the topical treatment of elevated intraocular pressure

Similar Documents

Publication Publication Date Title
US2554816A (en) Heterocyclic sulfonamides and methods of preparation thereof
US2595334A (en) Benzothiazolesulfonamides and method of preparing the same
US2045888A (en) Preparation of sulphene amides
US2783241A (en) S-acylimino-x-substituted-az-i
NO770161L (en) THIAZOLIDINE DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION.
US2455894A (en) Production of 1-mono-and 1, 2-disubstituted-3-cyanoguanidines
US2603649A (en) Heterocyclic sulfonamides and method of preparing the same
US2503861A (en) 2-(mercaptoacetamido)-benzothiazole and its s-acetyl derivative
DE915809C (en) Process for the preparation of heterocyclic sulfonamides
US2783240A (en) Heterocyclic sulfonamides
US2577231A (en) Diazine sulfonamides and methods of
US2992225A (en) Certain 4-(5-nitro-2-furyl)-thiazoles
US3097240A (en) Novel sulfonyl-ureas
US3244723A (en) Certain 4-aminothiazole compounds and their preparation
US2542856A (en) N-thiadiazolyl-4-iodobenzenesulfonamides
US2763660A (en) 1,3,4-oxadiazole-sulfonamides
US2945047A (en) Thiosemicarbazides
US2525321A (en) Hydroxybenzenesulfonamidoisoxazoles and preparation of same
US2348917A (en) Process for the manufacture of mercaptothiazolines
US2535971A (en) 1-carbalkoxy-4-substituted piperazines
US2674614A (en) Thiocarbhydrazine compounds
US2850503A (en) Preparation of methyl and ethyl n-
US2721204A (en) Derivatives of 1, 3, 4-thiadiazole-5-sulfonamides
IL28401A (en) Arylsulfonyl ureas,their manufacture and pharmaceutical compositions containing them
NO133892B (en)